tbuckley/cabot-search huggingface dataset:
Time interval between radium-223 (<sup>223</sup>Ra) therapy and Lutetium-177–prostate-specific membrane antigen (<sup>177</sup>Lu-PSMA) treatment and outcomes in the RALU study.
Authors: Kambiz Rahbar, Markus Essler, Matthias Eiber, Christian la Fougère, Vikas Prasad, Kim M. Pabst, Wolfgang Peter Fendler, Philipp Rassek, Ergela Hasa, Helmut Dittmann, Ralph A. Bundschuh, Milena Kurtinecz, Anja Schmall, Frank Verholen, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2023)

73 Background: 223 Ra and 177 Lu-PSMA-617 both prolong overall survival (OS) in different mCRPC settings. The observational, retrospective study, RALU, investigated safety and clinical outcomes of sequential 223 Ra/ 177 Lu-PSMA therapy in patients (pts) with mCRPC. This analysis evaluated the association of time interval between 223 Ra and 177 Lu-PSMA treatments and safety and OS outcomes of 177 Lu-PSMA. Methods: Retrospective data were collected from 2021–22 in German nuclear medicine centers for all pts receiving 177 Lu-PSMA with prior history of 223 Ra therapy. Time intervals were &lt;6 months (mo) (Group [Grp]1) or ≥6 mo (Grp 2) from last 223 Ra dose to first 177 Lu-PSMA dose. Results: 42 pts received 177 Lu-PSMA within 6 mo after 223 Ra (Grp 1) and 90 pts received 223 Ra ≥6 mo prior to 177 Lu-PSMA (Grp 2). Baseline characteristics prior to 177 Lu-PSMA therapy were, respectively: median ages 72 and 74 years; 57% and 63% with Eastern Cooperative Oncology Group performance status (ECOG PS) 1, 43% and 37% with ECOG PS 2; median prostate-specific antigen (PSA) values were 366 and 268 ng/ml, and median alkaline phosphatase (ALP) values were 133 and 149 U/L; 40% and 64% received ≥4 life prolonging therapies before starting 177 Lu-PSMA. All pts had prior 223 Ra; 57% and 77% received 6 223 Ra injections; other prior therapies were abiraterone (60%, 77%), enzalutamide (50%, 78%), docetaxel (71%, 76%) and cabazitaxel (17%, 26%). Prior to 177 Lu-PSMA, 24% and 29% of pts had visceral metastases. 45% and 52% of pts received ≥4 177 Lu-PSMA cycles. From 177 Lu-PSMA start to ≤30 days post last dose, 71% and 82% of pts had treatment-emergent adverse events (TEAEs) of any grade; most common were fatigue (12%, 7%), nausea (12%, 8%) and dry mouth (7%, 18%); 36% and 24% of pts had grade 3–4 TEAEs; excluding laboratory abnormalities, osteonecrosis of the jaw was the most frequent grade 3–4 TEAE (5%, 2%). Grade 3–4 laboratory abnormalities ( 177 Lu-PSMA start to ≤90 days post last dose) are shown; treatment-related deaths were reported for 2% and 4% of pts. AEs led to treatment delays in 10% and 9% of pts. Median OS from start of 177 Lu-PSMA was 12.0 mo (95% CI, 8.8–19.9) in Grp 1 and 13.2 mo (95% CI, 10.0–15.9) in Grp 2. During 177 Lu-PSMA therapy, PSA response ≥50% occurred in 53% and 39% and ALP response ≥30% in 28% and 14% of pts, respectively. Conclusions: In this real-world setting, treating pts with 177 Lu-PSMA within 6 mo of completing 223 Ra was clinically feasible and well tolerated: no safety signals or concerns were seen. OS outcomes were similar in pts receiving 177 Lu-PSMA &lt;6 mo vs. pts receiving it ≥6 mo after completing 223 Ra. [Table: see text]
“It just makes sense to me”: Patient experiences with prostate MRI during prostate cancer active surveillance.
Authors: Ryan Sutherland, Cary Philip Gross, Xiaomei Ma, Farah Jeong, Tyler M Seibert, Matthew R. Cooperberg, William Catalona, Stacy Loeb, Dena Schulman-Green, Michael Leapman
Journal: Journal of Clinical Oncology (2023)

334 Background: Although prostate MRI is commonly used in the diagnosis, staging and active surveillance of prostate cancer, little is known about patient perspectives on MRI imaging. Methods: We performed a qualitative descriptive study consisting of in-depth, semi-structured interviews of patients with low and intermediate risk prostate cancer managed with active surveillance. Interviews focused on experiences with prostate MRI and MRI-ultrasound fusion biopsy during active surveillance monitoring. We purposively sampled patients who received prostate MRI as part of their clinical care, over-sampling Black and Latino men, and conducted interviews until thematic saturation. We performed conventional content analysis to analyze data. Results: The mean sample (n=20) age was 68 years (range 51-79). Fourteen (70%) participants identified as White, 5(25%) as Black, and 2(10%) as Hispanic/Latino. At diagnosis, 17 (85%) had a Gleason grade group 1, and 3 (15%) had a grade group 2 tumor. Overall, participants viewed prostate MRI as a valuable tool that accurately localizes and monitors prostate cancer over time. Prostate MRI was seen as central to active surveillance monitoring. We identified five thematic categories: (1) the experiential aspects of undergoing an MRI scan; (2) the experience of visualizing one’s own prostate and prostate cancer; (3) adequacy of provider explanations of MRI results; (4) confidence in prostate MRI in decision-making; and (5) the role of prostate MRI in longitudinal follow-up during active surveillance, including an interest using MRI to modify the timing of, or replace, prostate biopsy. Conclusions: These findings reveal that patients highly value prostate MRI as a tool that enhances the confidence in the initial diagnosis and monitoring of prostate cancer. This work can inform future studies to optimize the patient experience, education and counseling during active surveillance for prostate cancer.
Mapping distribution of brain metastases in renal cell carcinoma (RCC) and association with clinical features.
Authors: Yasser Ged, Ardit Feinaj, Mark Christopher Markowski, Anirudh Yerrapragada, Roy Elias, Chetan Bettegowda, Nirmish Singla, David Kamson
Journal: Journal of Clinical Oncology (2023)

727 Background: Brain metastases (BM) are frequently observed in metastatic RCC (mRCC) with a tendency to present with hemorrhagic BM. Distribution patterns of BM in RCC and associations with clinical outcomes are not well understood. Here we present a detailed distribution analysis in a surgically resected BM RCC cohort with a focus on clinically relevant associations. Methods: A retrospective analysis was performed on patients (pts) with mRCC who underwent craniotomy for BM at our institution. We reviewed gadolinium-enhanced MRI brain and CT head (if available) at the time of BM diagnosis. We assessed the presence of hemosiderin on MRI or hemorrhage on CT in the BM lesion and marked each at their corresponding anatomic location. Public brain atlases were used for distribution analysis. Overall survival (OS) from the date of BM diagnosis and CNS progression free survival (CNS-PFS) from the date of craniotomy were calculated. Results: A total of 67 BM were analyzed from 46 pts. 23 with synchronous BM, 9 with two and 6 with 3 concurrent BM. Most patients were male (n=35, 76%) with a median age at diagnosis of 63 years. Primary histology was clear cell in 42 pts (91%) and 10 pts (22%) had renal vein thrombosis (RVT) at primary diagnosis. IMDC scores at time of BM diagnosis were favorable in 20%, intermediate in 60% and poor in 20%. Hemosiderin (MRI) or hemorrhage (CT) was seen in 82% and 80% of BM, respectively. 55% of lesions were left sided, 45% frontal, 21% parietal, 18% occipital, 7% temporal and 6% cerebellar. Posterior circulation and posterior cerebral artery territories contained 42% and 34% of BM despite supplying only 30% and 16% of the brain volume, respectively. Patients with solitary BM had higher Karnofsky performance status (p=0.006) and lower disease burden (p=0.004) than those with multiple BM. Shorter CNS-PFS was seen in association with hemosiderin on MRI (log-rank p=0.04) and RVT in primary specimen (log-rank p=0.002). IMDC risk scores (log-rank p&lt;0.001) predicted OS. On multivariable OS analysis, BM lateralized to the right (HR 2.6, p=0.06), hemosiderin in BM (HR 6.5, p=0.02) and IMDC risk groups (intermediate HR 2.9, poor risk HR 25.6, p&lt;0.04) were independent prognostic factors for shorter OS. Conclusions: The above-presented lesion mapping method shows clinically relevant findings in RCC BM. Tumoral hemosiderin deposits appear a potential parameter to predict outcomes in RCC BM which deserve further study and validation.
Clinical characteristics, tumor genomic and transcriptomic profiles of patients (pts) with metastatic renal cell carcinoma (mRCC) who developed venous thromboembolism (VTE).
Authors: Haoran Li, Kamal Kant Kant Sahu, Georges Gebrael, Beverly Chigarira, Vinay Mathew Thomas, Yeonjung Jo, Shruti Adidam Kumar, Blake Nordblad, James Brundage, Nishita Tripathi, Nicolas Sayegh, Umang Swami, Neeraj Agarwal, Benjamin L. Maughan
Journal: Journal of Clinical Oncology (2023)

726 Background: VTE is a common complication in pts with mRCC. Identifying pts with mRCC at the highest risk of developing VTE may provide the rationale for initiating prophylactic anticoagulation. Methods: In this IRB-approved retrospective study, pts diagnosed with mRCC between 7/2012 and 7/2022 at Huntsman Cancer Institute at University of Utah were included. Variables evaluated were pts' clinical characteristics, treatment, and anticoagulation therapy. Pts with mRCC with VTE within 12 months after diagnosis were used as cases and those without VTE during the same period were used as control. The multivariable logistic model was used to assess risk factors of VTE. DeSeq2 analysis was implemented in Bioconductor Software to analyze differentially expressed genes based on the VTE. These results were subjected to gene ontology analysis in the TopGO software. All bioinformatic analysis was conducted in R-Studio, version 4.1.1. Results: Among 355 pts with mRCC, 53 pts developed VTE within 12 months after diagnosis (incidence rate: 14.9%). Pts of the two groups (with or without VTE) did not differ significantly when compared for age, gender, race, cytoreductive nephrectomy rate, clear cell histology, grade of tumor, IMDC risk factors (table). Pts who developed VTE had a higher BMI at diagnosis (31.7 vs. 29.1 kg/m 2 , p=0.03). In multivariate analysis, obesity (OR=1.06, [1.01-1.12], p=0.028) was associated with increased VTE risk. There was no significant difference of mutation rates in genomic panel. Transcriptomic analysis showed hormone metabolic, organic acid transport, extracellular matrix and structure organization (all p&lt;0.0001) are among the most significantly elevated pathways associated with VTE. Correlation of genomic and transcriptomic data with occurrence of VTE will be presented in the meeting. Conclusions: In this real-world population of pts with mRCC, VTE is more commonly associated with mRCC than what was previously reported in clinical trials. These hypothesis generating data, upon external validation, may provide guidance for clinical use of prophylactic anticoagulation therapy in pts with mRCC.[Table: see text]
Major adverse cardiovascular events after androgen deprivation therapy in patients with prostate cancer with hypercholesterolemia.
Authors: Przemyslaw Twardowski, Jacqueline Henry, Stuart Atkinson
Journal: Journal of Clinical Oncology (2023)

348 Background: Prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT) may experience major adverse cardiovascular events (MACE). It is unclear how much of MACE is caused by ADT itself. High cholesterol has been associated with lower MACE risk in older men, not on statin therapy. This study evaluates MACE risk after ADT initiation for patients with and without hypercholesterolemia using real-world data. Methods: US electronic medical records (2010-2020) of PCa patients (n=45,059) receiving LHRH agonist/antagonist injections were analyzed to calculate the risk of MACE since ADT initiation in patients with and without hypercholesterolemia. Hypercholesterolemia was defined as having taken hypercholesterolemia medication or diagnosis with hypercholesterolemia prior to the first MACE event after ADT start. Exclusion criteria included lack of ADT initiation date or MACE within six months prior to ADT initiation. MACE was defined as myocardial infarction, stroke, and death from any cause. Kaplan-Meier event-free survival curves and cox regression were used to compare MACE risk between patients with and without hypercholesterolemia. Results: The dataset contained 178,388 LHRH injection entries and 7,681 MACE. MACE risk was only 1.8% lower (19.0% vs 20.8%) after 4 years for patients with hypercholesterolemia compared to those without (across 10 years, unadjusted: HR=0.88, 95% CI [0.83, 0.92] and adjusted: HR=0.85, 95% CI [0.77, 0.94]). Conclusions: Patients with hypercholesterolemia appear to have slightly lower MACE rates. This may be due to the use of statins, which can reduce the incidence of CV events in a general population. Our analysis of data over the most recent decade from ~45,000 PCa patients is likely an accurate reflection of the real world. Clinicians should monitor PCa patients with underlying CV risk factors and help educate them on lifestyle changes that could impact treatment outcomes.
Germline mutational profile in metastatic urothelial malignancy.
Authors: Emily Barry, Andre Luiz De Souza, Sheldon L. Holder, Galina Lagos, Anthony E. Mega, Benedito A. Carneiro, Ali Amin
Journal: Journal of Clinical Oncology (2023)

550 Background: 24% of patients with high-risk urothelial carcinoma have pathogenic germline mutations (Nassar, Genetics in Medicine 2020). In that study, demographics, metachronous/synchronous tumors, and family history did not differ between germline and sporadic cases of bladder cancer. We report herein the prevalence of actionable mutations and de novo metastatic disease in patients with germline mutations who developed metastatic urothelial carcinoma. Methods: We retrospectively analyzed a database of 90 patients with metastatic urothelial carcinoma (urethral, bladder, and upper tract disease) at our institution who had genetic testing performed on tumor specimens. T-student test was performed to calculate statistical significance for the distribution of age, while Chi-square test evaluated the frequency distribution of gender, actionable mutations, and de novo metastatic disease. Patients’ tumors were sequenced by a 700 gene panel for both somatic and germline mutations. Comprehensive chart review was performed to extract clinical data. Results: Out of the 90 patients reviewed, 11 (11.1%) had germline mutations. Of these patients, 5 had upper tract urothelial carcinoma, 5 had bladder cancer, and 1 had urethral cancer. Nine patients had pathogenic germline mutations: MUTYH, BRCA2 (each representing 1.8% of patients); APC, BRCA1, CDKN2A, FH, MSH2 (each representing 0.9% of patients). Two patients had germline mutations of unknown significance ( APC, CHEK2). Age (T-value 1.62053, p=1.08453), gender (Chi-square 0.0024, p=0.961037) or de novo metastatic presentation (Chi-square 0.5, p=0.4795) were not statistically significant between patients with germline and sporadic mutations. Somatic actionable mutations included ATR, BRCA2, BRAF, CDK12, ERBB2, FBXW7, FGFR3, HRAS, MTAP, and PIK3CA. Microsatellite instability high (MSI-H) status was only present in the patient with germline MSH2 mutation. PD-L1 expression was high (CPS ≥10) in 4 patients with germline mutations. Tumor mutational burden ranged from 1.1 to 28.4 mutations per Megabase. Conclusions: Our findings further define the clinical and genomic characteristics of patients with metastatic urothelial carcinoma and germline mutations in a tertiary center. Further investigation is warranted to validate these findings in national sequencing databases.
Relapse-free and overall survival in patients with non-seminomatous testicular germ cell tumours with teratoma-free primaries.
Authors: Pia Paffenholz, Georg Landwehr, Christoph Alexander Seidel, Annika Poch, Carsten Bokemeyer, Richard Cathomas, Pailin Pongratanakul, Andreas Hiester, Peter Albers, Martin Pichler, Susanne Krege, Isabella Syring, Julia Heinzelbecker, Tim Nestler, David Pfister, Axel Heidenreich
Journal: Journal of Clinical Oncology (2023)

421 Background: Characteristics and outcome of non-seminomatous testicular germ cell tumours (NSGCT) with teratoma-containing primaries are still under debate. Methods: We performed a retrospective analysis including 557 patients with metastatic NSGCT as a registry study within the "German Testicular Cancer Study Group". Results: Of the eligible 557 patients with NSGCT, 237 (42%) of all orchiectomy specimens had teratoma-containing primaries, while 320 (58%) were teratoma-free. Teratoma-containing primaries had a significantly higher clinical stage (p=0.002) and worse prognosis (p=0.051) compared to teratoma-free specimens. Lymph node metastasis were significantly larger before (4.5 vs 2.5cm; p&lt;0.001) and after chemotherapy (3.5 vs 2.5 cm; p&lt;0.001) in teratoma-containing primaries. Post-chemotherapy retroperitoneal lymph node dissection was performed in 57% of all patients. As teratoma-containing specimens revealed a significantly lower number of complete responses after chemotherapy, PC-PRLND was more often performed, with teratomatous elements being more often present in the PC-RPLND specimens compared to non-teratoma containing primaries. Kaplan-Meier estimates revealed that 19% of all patients relapsed during a median follow-up of 56 months [29-112] with a median time to relapse of 10 months. Teratoma-containing had a significantly lower relapse-free survival (RFS) compared to teratoma-free NSGCT (relapse rate 24% vs 16%, p=0.020). 8% (45/533) of all patients died due to their disease. There was no difference regarding the tumour-specific survival between teratoma-containing NSGCT and teratoma-free NSGCT when looking at the entire cohort of patients (8% vs. 9%, p=0.563), however median overall survival was not reached. Conclusions: In our study, NSGCT patients with teratoma-containing primaries showed a significantly higher clinical stage and worse prognosis at time of presentation compared to teratoma-free primaries. Furthermore, patients with teratoma-containing primaries showed a significantly worse relapse-free survival. Consequently, treating physicians should be aware of these patients portending a dismal prognosis and the presence of teratomatous elements might act as a reliable stratification tool for treatment decision in TGCT patients.
Final results of phase Ib/II study of durvalumab and guadecitabine in advanced clear cell renal cell carcinoma (ccRCC) and biomarker analysis.
Authors: Yousef Zakharia, Eric A. Singer, Satwik Acharyya, Rohan Garje, Monika Joshi, David J. Peace, Veera Baladandayuthapani, Claudia Laancette, Ilona Kryczek, Weiping Zou, Ajjai Shivaram Alva
Journal: Journal of Clinical Oncology (2023)

696 Background: Hypomethylating agents (HMA) can augment the anti-tumor immune response. Guadecitabine (G) is a novel HMA shown to induce a dose-dependent decrease of global DNA and gene-specific methylation in pre-clinical models. Methods: This is phase Ib/II clinical trial of Guadecitabine (G) and Durvalumab (D) in advanced ccRCC. Phase Ib tested two doses of G, de-escalated from 60 mg/m2 to 45 mg/m2 in combination with standard dose of D. Followed by two cohorts in phase II. Cohort 1 (C1, CPI naïve) allowed up to one prior line of treatment and Cohort 2 (C2, CPI refractory) enrolled patients with up to two prior systemic therapies including at least one CPI. Primary endpoint in phase 1b was safety, primary endpoint in phase II was overall response rate (ORR) and secondary endpoint of progression free survival (PFS) and overall survival (OS) and biomarkers evaluation. Results: Fifty-seven patients were enrolled, 42 were in C1 and 15 in C2. One dose limiting toxicity (DLT) of grade 3 neutropenia was noted with G 60 mg/m2. The combination of G 45 mg/m2 on days 1-5 along with D at 1500 mg on day 8, was deemed safe and the recommended phase II dose. Asymptomatic neutropenia was the most common adverse event (AE). Other AEs included thyroid dysfunction, diarrhea, pneumonitis, myalgia, and hepatotoxicity. No treatment-related deaths were reported. The ORR for C1 and C2 were 26% and 7% respectively. The median PFS for C1 and C2 were 18.4 and 3.9 months respectively. Median OS was not reached. Flow cytometry on peripheral blood (PB) collected before treatment demonstrated myeloid-derived suppressor cells (MDSC) to be inversely associated with response, showing the highest levels in progressive disease (PD) and the lowest in partial response (PR). Responders to treatment had the highest expression of IFN γ, IL-17 and RORyt in CD8+ T cells and lower Foxp3 expression in CD4+ T cells compared to non-responders. We observed a significant increase in serum CXCL9/CXCL10 with the study combination (p 0.00003 and p 0.000005 respectively) and this increase correlated with better clinical outcome. Conclusions: The combination of D and G has an acceptable toxicity profile and promising efficacy mainly PFS in CPI naïve ccRCC patients, that is worth further investigation in larger randomized clinical trial. Clinical trial information: NCT03308396 .
Molecular features and actionable targets for testicular germ cell tumors in a real-world setting.
Authors: Rafael Morales-Grimany, Cesar Delgado, Fady Baky, Armon Amini, Thomas Gerald, Rohit R Badia, Jacob Taylor, Luke Wang, Juan Javier-Desloges, Vitaly Margulis, Solomon L. Woldu, Amir Salmasi, Fred Millard, Rana R. McKay, Aditya Bagrodia
Journal: Journal of Clinical Oncology (2023)

430 Background: Molecular features of testicular germ cell tumors (GCT) in various clinical states (pre- vs post-chemotherapy, localized versus metastatic) may inform treatment options for patients with recurrence after definitive therapy. In his study, we describe molecular features and potential therapeutic targets in a cohort of patients with testicular GCT. Methods: We retrospectively examined clinicopathologic and next-generation sequencing (NGS) data from 27 patients with GCT. Tumors were sequenced using the Tempus|xT solid tumor assay, which includes DNA sequencing of 595-648 genes at 500x coverage and RNA sequencing for all human coding genes. Tumor mutational burden (TMB) was measured for all tumors and PD-L1 levels were assessed qualitatively by 22C3 pharmDx immunohistochemistry assay in 8 patients. All genetic variants detected were quantified and analyzed to identify potentially actionable targets. Results: We identified 13 (48%) stage I GCT, 11 (41%) stage II, and 3 (11%) stage III. There were 7 seminomas and 20 nonseminomas. 12 tumor specimen resections were obtained from orchiectomy, and 15 from retroperitoneal lymph node dissection (RPLND), of which, 8 were chemotherapy-naïve and 7 were post-chemotherapy. Chemo-naïve RPLND histology showed a combination of teratoma, seminoma, and mixed GCT, while post-chemo histology revealed 6 teratomas and 9 benign pathologies. The median TMB for the cohort was 0.75 mutations/megabase. Somatic mutations were identified in 55% of patients and most commonly within: KRAS (25.9%), KIT (11.1%), and PIK3CB (7.4%). PD-L1 expression was observed in 75% of the tumors measured (60% positivity at stage I and 100% positivity at stage III). Microsatellite stability was stable in 18 tumors tested. DNA alterations- [single base pair substitutions, insertions, and deletions]- in KRAS (GTPase) proto-oncogenes were detected in 7 tumors and tyrosine kinase receptor gene variants (KIT, P1K3CB) were found at similar frequencies across disease stages. Whole transcriptome NGS RNA expression assays were performed on 21 untreated specimens revealing overexpression of MTOR (33%), MAPK1(14%), and MET (8.0%). Actionable targets with FDA-approved therapies in other organ tissues were detected in 11 patients (40.7%). Incidental germline mutations, including MSH6, RB1, and MSH2, were identified in 9 patients though all were variants of unknown significance. Conclusions: In our study, a significant proportion of patients had potentially actionable molecular targets across the disease spectrum. The identified genetic alterations provide a genomic landscape for risk stratification, future therapies, and molecularly informed treatment paradigms for GCT patients.